The present invention relates generally to 5-fluoro- and 8-fluoro-trimetoquinol compounds and the processes for their manufacture, and pharmaceutical preparations thereof.
The invention further relates to the use of such compounds to increase the .beta..sub.2 -adrenergic activity while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The invention further relates to the pharmaceutical use of such compounds in the treatment of pulmonary and cardiovascular diseases. In particular, the compounds of the invention are useful in the treatment of lower respiratory tract disorders, such as for example, asthma, allergen-induced bronchospasms or emphysema, or for the treatment of hypertension, or for the treatment of thromboembolic disorders.
The adrenergic nervous system is one portion of the autonomic nervous system, which regulates or controls the so-called vegetative or involuntary functions of the body. This nervous system innervates the major organs of the body, eg., the lungs and heart. The neurotransmitters released by the nerve terminals interact with receptors in the tissue of the various organs of the body to produce specific biological responses. The primary receptors upon which adrenergic stimulants act, have been divided into the .alpha.- and .beta.-adrenergic receptors. The .beta.-receptors are associated with smooth muscle relaxation in the lower respiratory tract, relaxation of blood vessels in skeletal muscle, cardiac muscle stimulation, and lipolysis. The receptors associated with .beta.-responses have been further classified as .beta..sub.1 (cardiac stimulation and lipolysis) or .beta..sub.2 (bronchodilation and vasodilation). There has been considerable effort to develop selective .beta..sub.2 adrenergic stimulants. Such compounds would retain the important bronchodilation activity while being devoid of the cardiovascular, gastrointestinal, and central nervous system side effects produced by compounds possessing significant .alpha.- and .beta..sub.1 -adrenergic receptor stimulation.
One adrenergic stimulant used extensively in the therapy of asthma has been isoproterenol. In the past, isoproterenol was popular because of its prompt and intense action in bringing about bronchodilation after inhalation. Unfortunately isoproterenol possesses little tissue selectivity and stimulates both .beta..sub.1 - and .beta..sub.2 -adrenergic receptors. The stimulation of the myocardium may lead to undesirable tachycardia, increase in cardiac output and an elevation in blood pressure. Since isoproternol dilates previously constricted blood vessels in the lung, exaggerated ventilation blood flow inequality may result in a worsening hypoxia. Although isoproterenol has a fast onset of action (2-5 min), and a relatively short duration of action (averaging 1.5-2 h), some patients may become tolerant to its action. Excessive use of pressurized aerosols containing isoproterenol can not only lead to tolerance but may also be associated with an increase in deaths due to excessive .beta..sub.1 -stimulation of the heart.
Another well-known adrenergic stimulant is epinephrine which was the earliest catecholamine to be used for its bronchodilation activity. Epinephrine stimulates both .alpha.- and .beta.-adrenergic receptors to about the same degree. There are differences in the biological activity of the optical isomers of a number of adrenergic drugs closely related to epinephrine. R-(-)-epinephrine, the naturally occurring form, is more active than S-(+)-epinephrine on both .alpha.- and .beta.-adrenergic receptors. R-(-)-epinephrine, which can be extracted from adrenal glands is the isomer used as a drug. Epinephrine can also be synthesized wherein racemic epinephrine is resolved using (+)-tartaric acid to give R-(-)-epinephrine. Epinephrine is similar to isoproterenol in that it does not show selectivity in activating .beta.-adrenergic receptors. Because of this nonselectivity and its ability to activate .alpha.-adrenergic receptors, epinephrine may produce a variety of side effects including tachycardia, elevated blood pressure, headache, and tremors.
Modifications of epinephrine have been carried out in an attempt to produce a selective .beta.-adrenergic agonist; for example, Kirk et al., in J. Med. Chem., 22: 1493, 1979, reported that fluorine substitution at the 2-position of norepinephrine produces a selective .beta.-adrenergic agonist, while the 6-fluoro analog of norephinephrine produces a selective .beta.-adrenergic agonist. However, the corresponding 2-fluoro and 6-fluoro-dopamine analogs do not show selectivity for adrenergic receptors.
Another adrenergic stimulant is trimetoquinol 1, a bronchoselective .beta.-adrenoceptor agonist of the tetrahydroisoquinoline class, which is useful for the treatment of moderate bronchial asthma. ##STR2## In addition to .beta.-adrenoceptor activity, trimetoquinol 1 blocks endoperoxide/thromboxane arachidonic acid-mediated in vitro aggregation of human platelets. The S(-)-isomer of trimetoquinol is marketed in Japan as a bronchodilator for the treatment of asthma. However, the trimetoquinol 1 has the undesirable effect of also increasing the .beta..sub.1 -adrenergic activity which stimulates the heart.
Certain trimetoquinol analogs are described as having been prepared in Miller et al., J. Med. Chem., 19: 763-766, 1976; Osei-Gyimah et al., J. Med. Chem., 21: 1173-1178, 1978; Piascik et al., Biochem. Pharmacol., 28: 1807-1810, 1979, and Life Sci., 24: 2433-2440, 1979; Mukhopadhyay et al., Eur. J. Pharmacol., 77: 209-219, 1982; and Mukhopadhyay et al., J. Pharmacol. Exp. Ther., 232: 1-9, 1985; in an attempt to obtain more potent and organ selective .beta.-adrenoceptor agents.
Although much effort has been made to provide an orally active, direct acting .beta..sub.2 -adrenergic agonist with rapid onset and long duration of action, literature contains no references to fluorine substituted trimetoquinol analogs, and until now no attempt has been made to substitute fluorine on the catechol segment of trimetoquinol in order to separate .beta..sub.2 - from .beta..sub.1 -adrenergic activity.